Extracellular Vesicle-Based mRNA Therapeutics and Vaccines

Messenger RNA (mRNA) therapeutics and vaccines have recently gained particular prominence following the COVID-19 epidemic. However, clinical translation of mRNAs is critically dependent on efficient and safe delivery in vivo. Currently, a plethora of mRNA delivery technology platforms (such as lipid nanoparticles) have been developed and have achieved stunning success. Nevertheless, many challenges remain to be overcome, including immunogenicity and toxicities, excessive liver accumulation, limited endosomal escape ability, low tissue bioavailability, poor mucosal immunity, and the need for cold chain storage. In recent years, extracellular vesicles (EVs) have emerged as an attractive mRNA delivery platform due to their favorable properties, such as low immunogenicity, natural capability to deliver RNAs, intrinsic targeting capacity, and the ability to negotiate with physiological barriers. In this review, we discuss the latest efforts to harness EVs for mRNA delivery and elaborate the behind mechanisms, aiming to offering insights into the rational design of effective and safe EV-based mRNA therapeutics and vaccines for biomedical applications. Additionally, we provide an overview of EV biogenesis, composition, cellular internalization, and their superiorities and challenges for mRNA delivery, with special emphasis on the state-of-the-art methodologies for packaging EVs with mRNAs.